SFEIES24 Oral Poster Presentations Oral Posters 2 – Diabetes/Obesity/Metabolism 1 (4 abstracts)
11β-HSD1 inhibitor efficacy in type 2 diabetes is cortisol-dependent
Atinuke Wilton-Waddell 1 , Layal Abi Farraj 2 , Elton JR. Vasconcelos 1 , Emily Byrne 1 , Angela E. Taylor 3 , Adrian Freeman 4 , Damla Etal 4 , Paul M. Stewart 1 , Wiebke Arlt 3 , Ramzi Ajjan 1 & Ana Tiganescu 1
1University of Leeds, Leeds, United Kingdom; 2UCLA, Los Angeles, USA; 3University of Birmingham, Birmingham, United Kingdom; 4AstraZeneca, Cambridge, United Kingdom
Cortisol excess drives multiple adverse effects including hypertension, dyslipidemia, and delayed wound healing. Activation of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has shown promise as a therapeutic target for these comorbidities but clinical progress has been hampered by variable 11β-HSD1 inhibitor efficacy. Transcriptomic profiling by RNA-seq found 611 11β-HSD1 target genes in primary skin fibroblasts (n = 3), and 814 target genes in skin biopsies from people with type 2 diabetes treated for 35 days with the selective 11β-HSD1 inhibitor AZD4017 (400 mg bi-daily, n = 11) or placebo (n = 6). Targets included genes involved in wound healing (e.g., MMP1, VEGFA, CD163, SOX4, KRT5), epidermal integrity (e.g., CLDN3, DSC2, DSG2, SPHK2) extracellular matrix remodelling (e.g., TNC, LOXL1, TIMP3, HAS3, P3H3, PLOD1), coagulation (e.g., F3, PROS1, SERPINE1, ADAMTS13, ST3GAL4), lipid metabolism (e.g., IRS2, LEP, HMGCS2, APOB, DEGS2), and inflammation (e.g., IL1B, IL6, PTGS2, CX3CL1). Serum steroid profiles were measured by liquid chromatography-mass spectrometry. Changes in expression of 45 11β-HSD1 skin target genes, blood pressure, lipids, and wound healing correlated (r >0.3 or <-0.3, P < 0.05, n = 17) with changes in 1) cortisol levels (serum cortisol/dehydroepiandrosterone sulfate) and 2) peripheral 11β-HSD1 activity (serum cortisol/cortisone). People with low baseline cortisol levels treated with AZD4017 (n = 3) were more comparable to those treated with placebo, whereas placebo-treated people with a reduction in cortisol levels (n = 2) were more comparable to those treated with AZD4017. These findings pave the way for more effective targeting of 11β-HSD1 inhibitor treatment, improving the accuracy of future clinical studies, alongside new mechanistic insights for 11β-HSD1 in delayed wound healing and cardiovascular comorbidities. Larger trials are now warranted to fully explore the therapeutic potential of 11β-HSD1 inhibitors.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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